The capacity of inbred mice to resist infections with the malaria parasite Plasmodium Yoelii is determined by a dynamic interplay of host and parasite genes. Thus, a single strain of mouse may be relatively resistant to infection with an avirulent isolate of P. Yoelii, yet be exquisitely susceptible to infection with a virulent isolate of the same parasite species. The converse also applies. Both MHC genes, and genes outside the MHC influence that host response to infection. Experiments are proposed to identify and thoroughly characterize the host genes which influence the immune response following infection. Parasite-specific humoral and cellular immune responses of genetically characterized susceptible and resistant mouse strains will be compared throughout the course of infection with different parasite isolates, and genetic differences between the virulent and avirulent malaria isolates will be assessed at the protein and nucleic acid levels. The long range goal of this project is to explain how a single set of host genes can regulate responses which mediate increased susceptibility to infection with one isolate of P. Yoelii, yet render the host comparatively resistant to infection with a related isolate of the same parasite species.